DOCSLIB.ORG

High-Throughput Genetic Testing in ALS: the Challenging Path of Variant Classification Considering the ACMG Guidelines

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
High-Throughput Genetic Testing in ALS: the Challenging Path of Variant Classification Considering the ACMG Guidelines G C A T T A C G G C A T genes Article High-Throughput Genetic Testing in ALS: The Challenging Path of Variant Classification Considering the ACMG Guidelines 1,2, 1,2, , 1,2 3 Serena Lattante y , Giuseppe Marangi * y , Paolo Niccolò Doronzio , Amelia Conte , Giulia Bisogni 3, Marcella Zollino 1,2 and Mario Sabatelli 3,4 1 Section of Genomic Medicine, Department of Life Sciences and Public Health, Faculty of Medicine and Surgery, Catholic University of the Sacred Heart, 00168 Roma, Italy; [email protected] (S.L.); [email protected] (P.N.D.); [email protected] (M.Z.) 2 Complex Operational Unit of Medical Genetics, Department of Laboratory and Infectious Disease Sciences, A. Gemelli University Hospital Foundation IRCCS, 00168 Roma, Italy 3 Adult NEMO Clinical Center, Complex Operational Unit of Neurology, Department of Aging, Neurological, Orthopedic and Head-Neck Sciences, A. Gemelli University Hospital Foundation IRCCS, 00168 Roma, Italy; [email protected] (A.C.); [email protected] (G.B.); [email protected] (M.S.) 4 Section of Neurology, Department of Neuroscience, Faculty of Medicine and Surgery, Catholic University of the Sacred Heart, 00168 Roma, Italy * Correspondence: [email protected]; Tel.: +39-0630154606 These authors contributed equally to this work. y Received: 14 August 2020; Accepted: 22 September 2020; Published: 24 September 2020 Abstract: The development of high-throughput sequencing technologies and screening of big patient cohorts with familial and sporadic amyotrophic lateral sclerosis (ALS) led to the identification of a significant number of genetic variants, which are sometimes difficult to interpret. The American College of Medical Genetics and Genomics (ACMG) provided guidelines to help molecular geneticists and pathologists to interpret variants found in laboratory testing. We assessed the application of the ACMG criteria to ALS-related variants, combining data from literature with our experience. We analyzed a cohort of 498 ALS patients using massive parallel sequencing of ALS-associated genes and identified 280 variants with a minor allele frequency < 1%. Examining all variants using the ACMG criteria, thus considering the type of variant, inheritance, familial segregation, and possible functional studies, we classified 20 variants as “pathogenic”. In conclusion, ALS’s genetic complexity, such as oligogenic inheritance, presence of genes acting as risk factors, and reduced penetrance, needs to be considered when interpreting variants. The goal of this work is to provide helpful suggestions to geneticists and clinicians dealing with ALS. Keywords: amyotrophic lateral sclerosis; ACMG guidelines; high-throughput genetic testing; gene panel sequencing 1. Introduction In recent years, the fast and steady development of high-throughput technologies for genetic analysis dramatically changed the diagnostic approach in medical genetics and research strategies in related scientific fields. Consequently, these methods also impacted the study of amyotrophic lateral sclerosis (ALS), a neurodegenerative adult onset disease involving motor neurons in the cerebral cortex, brainstem, and spinal cord. Genetic factors play an important role in ALS pathogenesis, especially in familial amyotrophic lateral sclerosis cases (FALS), where a Mendelian dominant inheritance Genes 2020, 11, 1123; doi:10.3390/genes11101123 www.mdpi.com/journal/genes Genes 2020, 11, 1123 2 of 31 pattern with high penetrance is detectable. FALS represent about 10% of all cases and the genetic cause has been identified in 70% of them. Although the remaining 90% of cases occur sporadically (sporadic amyotrophic lateral sclerosis, SALS) in the general population, a genetic cause or Mendelian etiology has been identified in 11% [1]. Thanks to the advent of next-generation sequencing (NGS) technologies and to the extension of the screening to SALS cases, more than 100 genes have been associated with ALS to date, with thousands of variants. Progressively, NGS was introduced in clinical settings and genetic testing is increasingly offered to ALS patients, with relevant psychological, social, and ethical consequences, which need to be considered. Hence, genetic counseling has become an essential step to manage ALS patients, not only in familial, but also in sporadic cases [2]. An important issue raised by the availability of high-throughput genetic analyses is the interpretation of the variant consequences and, from a clinical point of view, the need for a correct variant classification in either of the two main categories: Pathogenic or benign. To that purpose, international research groups attempted to reach consensus about criteria, which should be used for classification. The guidelines proposed by the American College of Medical Genetics and Genomics (ACMG) [3] are, undoubtedly, the most universally used for Mendelian disorders. By applying these criteria, variants should be classified in five different categories: “Pathogenic”, “likely pathogenic”, “uncertain significance”, “likely benign”, and “benign”. Recently, researchers used the ACMG standards to interpret variants found in ALS patients [4–6]. In this study, we discuss the application of ACMG guidelines to ALS, combining data reported in literature with results obtained from a large ALS cohort, screened with gene panel sequencing over a four-year period. The ACMG criteria are summarized in Table1. Table 1. List of the American College of Medical Genetics and Genomics (ACMG) criteria, with their acronyms, relevance in amyotrophic lateral sclerosis (ALS), and considerations about their application in ALS variant interpretation. Considerations for Their Code Criteria Level of Evidence Relevance in ALS Application in ALS Null variant (nonsense, frameshift, So far, applicable for variants in canonical splice sites, etc.) in a gene PVS1 Very strong ++ following genes (in ALS): ALS2, for which loss of function is a SPG11, TBK1, OPTN common mechanism of disease Frequently applicable for genes Same amino acid change as a more extensively investigated than PS1 Strong ++ previously established variant others, e.g., SOD1, FUS, and TARDBP Parental testing rarely performed on De novo variant in a patient with routine basis. To be assessed mainly PS2 Strong + the disease and no family history in early-onset cases (e.g., FUS-related ALS) Functional studies already available Well-established functional studies for a large series of variants, but PS3 supportive of a damaging effect on Strong + well-established tools are still the gene or gene product missing for routine assessment of variant role Data from large cohorts of patients The prevalence of the variant in and controls are already publicly affected individuals is significantly available. Larger studies are still PS4 Strong ++ increased compared with the necessary to reach statistical prevalence in controls significance for as many variants as possible Genes 2020, 11, 1123 3 of 31 Table 1. Cont. Considerations for Their Code Criteria Level of Evidence Relevance in ALS Application in ALS Located in a mutational hotspot Easy to apply for variants in genes and/or critical and well-established such as FUS, TARDBP, and KIF5A. PM1 Moderate ++ functional domain without Further studies needed for an benign variation extension of the list To be considered in any case. Consensus is missing about allele frequency thresholds (i.e., variants PM2 Absent from population controls Moderate + responsible for ALS can be found in general population at low frequencies) To be considered when variants in For recessive disorders, detected in PM3 Moderate + genes responsible for recessive trans with a pathogenic variant forms of ALS are found Protein length changes as a result of A small subset of variants found to in-frame deletions/insertions in a PM4 Moderate + date belong to this category, and non-repeat region or their role is still not well-defined stop-loss variant Novel missense at an amino acid Frequently applicable for genes residue where a different PM5 Moderate ++ more extensively investigated, e.g., pathogenic missense change has SOD1, FUS, and TARDBP been seen before Parental testing rarely performed on Assumed de novo, without routine basis. To be assessed mainly PM6 confirmation of paternity Moderate + in early-onset cases (e.g., and/or maternity FUS-related ALS) Cosegregation with disease in To be used for familial cases. multiple affected family members in Families with a larger number of PP1 Supporting* ++ a gene definitively known to cause affected members would allow for the disease increased significance Missense variant in a gene that has a low rate of benign missense PP2 variation and in which missense Supporting ++ Fulfilled for most ALS genes variants are a common mechanism of disease Multiple lines of computational Routinely used for variant PP3 evidence support a deleterious Supporting ++ evaluation in ALS effect on the gene or gene product Applicable only in specific Patient’s phenotype or family situations (i.e., large families with history is highly specific for a PP4 Supporting + apparently Mendelian inheritance disease with a single or suggestive phenotypes, such as genetic etiology juvenile forms) Reputable source reports variant as pathogenic, but the evidence is not Evidence strength depending on PP5 Supporting* ++ available to the laboratory to number and details of reports perform an independent evaluation Allele frequency is >5% in BA1 Stand-alone ++ To be considered for any variant general
Load more

Recommended publications
  • Computational Genome-Wide Identification of Heat Shock Protein Genes in the Bovine Genome [Version 1; Peer Review: 2 Approved, 1 Approved with Reservations]
    F1000Research 2018, 7:1504 Last updated: 08 AUG 2021 RESEARCH ARTICLE Computational genome-wide identification of heat shock protein genes in the bovine genome [version 1; peer review: 2 approved, 1 approved with reservations] Oyeyemi O. Ajayi1,2, Sunday O. Peters3, Marcos De Donato2,4, Sunday O. Sowande5, Fidalis D.N. Mujibi6, Olanrewaju B. Morenikeji2,7, Bolaji N. Thomas 8, Matthew A. Adeleke 9, Ikhide G. Imumorin2,10,11 1Department of Animal Breeding and Genetics, Federal University of Agriculture, Abeokuta, Nigeria 2International Programs, College of Agriculture and Life Sciences, Cornell University, Ithaca, NY, 14853, USA 3Department of Animal Science, Berry College, Mount Berry, GA, 30149, USA 4Departamento Regional de Bioingenierias, Tecnologico de Monterrey, Escuela de Ingenieria y Ciencias, Queretaro, Mexico 5Department of Animal Production and Health, Federal University of Agriculture, Abeokuta, Nigeria 6Usomi Limited, Nairobi, Kenya 7Department of Animal Production and Health, Federal University of Technology, Akure, Nigeria 8Department of Biomedical Sciences, Rochester Institute of Technology, Rochester, NY, 14623, USA 9School of Life Sciences, University of KwaZulu-Natal, Durban, 4000, South Africa 10School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, 30032, USA 11African Institute of Bioscience Research and Training, Ibadan, Nigeria v1 First published: 20 Sep 2018, 7:1504 Open Peer Review https://doi.org/10.12688/f1000research.16058.1 Latest published: 20 Sep 2018, 7:1504 https://doi.org/10.12688/f1000research.16058.1 Reviewer Status Invited Reviewers Abstract Background: Heat shock proteins (HSPs) are molecular chaperones 1 2 3 known to bind and sequester client proteins under stress. Methods: To identify and better understand some of these proteins, version 1 we carried out a computational genome-wide survey of the bovine 20 Sep 2018 report report report genome.
    [Show full text]
  • ALS2CR2 (STRADB) 406-418) Goat Polyclonal Antibody – AP08962PU-N
    OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for AP08962PU-N ALS2CR2 (STRADB) 406-418) Goat Polyclonal Antibody Product data: Product Type: Primary Antibodies Applications: ELISA, IHC, WB Recommended Dilution: ELISA: 1/32000. Immunohistochemistry on Paraffin Sections: 3.75 µg/ml. Western Blot: 1 - 3 µg/ml. Reactivity: Canine, Human Host: Goat Clonality: Polyclonal Immunogen: Synthetic peptide from C-terminus of human ALS2CR2 Specificity: This antibody reacts to STE20-Related Kinase Adaptor Beta (STRADB/ALS2CR2) at aa 406-418. It is expected to recognise both human isoforms: ILPIP-alpha (NP_061041.2) and ILPIP-beta (AAF71042.1). Formulation: Tris saline buffer, pH 7.3, 0.5% BSA, 0.02% sodium azide State: Aff - Purified State: Liquid purified Ig Concentration: lot specific Purification: Immunoaffinity Chromatography Conjugation: Unconjugated Storage: Store the antibody undiluted at 2-8°C for one month or (in aliquots) at -20°C for longer. Avoid repeated freezing and thawing. Stability: Shelf life: one year from despatch. Database Link: Entrez Gene 55437 Human Q9C0K7 This product is to be used for laboratory only. Not for diagnostic or therapeutic use. View online » ©2021 OriGene Technologies, Inc., 9620 Medical Center Drive, Ste 200, Rockville, MD 20850, US 1 / 3 ALS2CR2 (STRADB) 406-418) Goat Polyclonal Antibody – AP08962PU-N Background: Amyotrophic lateral sclerosis 2 (juvenile) chromosome region, candidate 2, is connected to transferase/kinase activity and ATP binding, it has recently been shown to interact with XIAP, a member of the IAP (Inhibitor of Apoptosis) protein family.
    [Show full text]
  • Genome-Wide Analyses Identify KIF5A As a Novel ALS Gene
    This is a repository copy of Genome-wide Analyses Identify KIF5A as a Novel ALS Gene.. White Rose Research Online URL for this paper: http://eprints.whiterose.ac.uk/129590/ Version: Accepted Version Article: Nicolas, A, Kenna, KP, Renton, AE et al. (210 more authors) (2018) Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron, 97 (6). 1268-1283.e6. https://doi.org/10.1016/j.neuron.2018.02.027 Reuse This article is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs (CC BY-NC-ND) licence. This licence only allows you to download this work and share it with others as long as you credit the authors, but you can’t change the article in any way or use it commercially. More information and the full terms of the licence here: https://creativecommons.org/licenses/ Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request. [email protected] https://eprints.whiterose.ac.uk/ Genome-wide Analyses Identify KIF5A as a Novel ALS Gene Aude Nicolas1,2, Kevin P. Kenna2,3, Alan E. Renton2,4,5, Nicola Ticozzi2,6,7, Faraz Faghri2,8,9, Ruth Chia1,2, Janice A. Dominov10, Brendan J. Kenna3, Mike A. Nalls8,11, Pamela Keagle3, Alberto M. Rivera1, Wouter van Rheenen12, Natalie A. Murphy1, Joke J.F.A. van Vugt13, Joshua T. Geiger14, Rick A. Van der Spek13, Hannah A. Pliner1, Shankaracharya3, Bradley N.
    [Show full text]
  • Absence of NEFL in Patient-Specific Neurons in Early-Onset Charcot-Marie-Tooth Neuropathy Markus T
    ARTICLE OPEN ACCESS Absence of NEFL in patient-specific neurons in early-onset Charcot-Marie-Tooth neuropathy Markus T. Sainio, MSc, Emil Ylikallio, MD, PhD, Laura M¨aenp¨a¨a, MSc, Jenni Lahtela, PhD, Pirkko Mattila, PhD, Correspondence Mari Auranen, MD, PhD, Johanna Palmio, MD, PhD, and Henna Tyynismaa, PhD Dr. Tyynismaa [email protected] Neurol Genet 2018;4:e244. doi:10.1212/NXG.0000000000000244 Abstract Objective We used patient-specific neuronal cultures to characterize the molecular genetic mechanism of recessive nonsense mutations in neurofilament light (NEFL) underlying early-onset Charcot- Marie-Tooth (CMT) disease. Methods Motor neurons were differentiated from induced pluripotent stem cells of a patient with early- onset CMT carrying a novel homozygous nonsense mutation in NEFL. Quantitative PCR, protein analytics, immunocytochemistry, electron microscopy, and single-cell transcriptomics were used to investigate patient and control neurons. Results We show that the recessive nonsense mutation causes a nearly total loss of NEFL messenger RNA (mRNA), leading to the complete absence of NEFL protein in patient’s cultured neurons. Yet the cultured neurons were able to differentiate and form neuronal networks and neuro- filaments. Single-neuron gene expression fingerprinting pinpointed NEFL as the most down- regulated gene in the patient neurons and provided data of intermediate filament transcript abundancy and dynamics in cultured neurons. Blocking of nonsense-mediated decay partially rescued the loss of NEFL mRNA. Conclusions The strict neuronal specificity of neurofilament has hindered the mechanistic studies of re- cessive NEFL nonsense mutations. Here, we show that such mutation leads to the absence of NEFL, causing childhood-onset neuropathy through a loss-of-function mechanism.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Integrated Transcriptome and Methylome Analysis in Youth at High Risk for Bipolar Disorder: a Preliminary Analysis
    OPEN Citation: Transl Psychiatry (2017) 7, e1059; doi:10.1038/tp.2017.32 www.nature.com/tp ORIGINAL ARTICLE Integrated transcriptome and methylome analysis in youth at high risk for bipolar disorder: a preliminary analysis GR Fries1, J Quevedo1,2,3,4, CP Zeni2, IF Kazimi2, G Zunta-Soares2, DE Spiker2, CL Bowden5, C Walss-Bass1,2,3 and JC Soares1,2 First-degree relatives of patients with bipolar disorder (BD), particularly their offspring, have a higher risk of developing BD and other mental illnesses than the general population. However, the biological mechanisms underlying this increased risk are still unknown, particularly because most of the studies so far have been conducted in chronically ill adults and not in unaffected youth at high risk. In this preliminary study we analyzed genome-wide expression and methylation levels in peripheral blood mononuclear cells from children and adolescents from three matched groups: BD patients, unaffected offspring of bipolar parents (high risk) and controls (low risk). By integrating gene expression and DNA methylation and comparing the lists of differentially expressed genes and differentially methylated probes between groups, we were able to identify 43 risk genes that discriminate patients and high-risk youth from controls. Pathway analysis showed an enrichment of the glucocorticoid receptor (GR) pathway with the genes MED1, HSPA1L, GTF2A1 and TAF15, which might underlie the previously reported role of stress response in the risk for BD in vulnerable populations. Cell-based assays indicate a GR hyporesponsiveness in cells from adult BD patients compared to controls and suggest that these GR-related genes can be modulated by DNA methylation, which poses the theoretical possibility of manipulating their expression as a means to counteract the familial risk presented by those subjects.
    [Show full text]
  • De Novo, Systemic, Deleterious Amino Acid Substitutions Are Common in Large Cytoskeleton‑Related Protein Coding Regions
    BIOMEDICAL REPORTS 6: 211-216, 2017 De novo, systemic, deleterious amino acid substitutions are common in large cytoskeleton‑related protein coding regions REBECCA J. STOLL1, GRACE R. THOMPSON1, MOHAMMAD D. SAMY1 and GEORGE BLANCK1,2 1Department of Molecular Medicine, Morsani College of Medicine, University of South Florida; 2Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA Received June 13, 2016; Accepted October 31, 2016 DOI: 10.3892/br.2016.826 Abstract. Human mutagenesis is largely random, thus large Introduction coding regions, simply on the basis of probability, represent relatively large mutagenesis targets. Thus, we considered Genetic damage is largely random and therefore tends to the possibility that large cytoskeletal-protein related coding affect the larger, functional regions of the human genome regions (CPCRs), including extra-cellular matrix (ECM) more frequently than the smaller regions (1). For example, coding regions, would have systemic nucleotide variants that a systematic study has revealed that cancer fusion genes, on are not present in common SNP databases. Presumably, such average, are statistically, significantly larger than other human variants arose recently in development or in recent, preceding genes (2,3). The large introns of potential cancer fusion genes generations. Using matched breast cancer and blood-derived presumably allow for many different productive recombina- normal datasets from the cancer genome atlas, CPCR single tion opportunities, i.e., many recombinations that would allow nucleotide variants (SNVs) not present in the All SNPs(142) for exon juxtaposition and the generation of hybrid proteins. or 1000 Genomes databases were identified. Using the Protein Smaller cancer fusion genes tend to be associated with the rare Variation Effect Analyzer internet-based tool, it was discov- types of cancer, for example EWS RNA binding protein 1 in ered that apparent, systemic mutations (not shared among Ewing's sarcoma.
    [Show full text]
  • Analysis of Shared Common Genetic Risk Between Amyotrophic Lateral Sclerosis and Epilepsy
    Neurobiology of Aging xxx (2020) 1.e1e1.e5 Contents lists available at ScienceDirect Neurobiology of Aging journal homepage: www.elsevier.com/locate/neuaging Negative results Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy Dick Schijvena,b,c, Remi Stevelinkd, Mark McCormackd,e, Wouter van Rheenena, Jurjen J. Luykxb, Bobby P.C. Koelemand, Jan H. Veldinka,*, on behalf of the Project MinE ALS GWAS Consortium International League Against Epilepsy Consortium on Complex Epilepsies a Department of Neurology and Neurosurgery, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands b Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands c Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands d Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands e Department of Molecular and Cellular Therapeutics, The Royal College of Surgeons in Ireland, Dublin, Ireland article info abstract Article history: Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the Received 23 September 2019 latest and largest genome-wide studies in amyotrophic lateral sclerosis (n ¼ 36,052) and epilepsy (n ¼ Received in revised form 31 January 2020 38,349) to determine genetic overlap between these conditions. First, we showed no significant ge- Accepted 10 April 2020 netic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases.
    [Show full text]
  • Neurofilaments: Neurobiological Foundations for Biomarker Applications
    Neurofilaments: neurobiological foundations for biomarker applications Arie R. Gafson1, Nicolas R. Barthelmy2*, Pascale Bomont3*, Roxana O. Carare4*, Heather D. Durham5*, Jean-Pierre Julien6,7*, Jens Kuhle8*, David Leppert8*, Ralph A. Nixon9,10,11,12*, Roy Weller4*, Henrik Zetterberg13,14,15,16*, Paul M. Matthews1,17 1 Department of Brain Sciences, Imperial College, London, UK 2 Department of Neurology, Washington University School of Medicine, St Louis, MO, USA 3 a ATIP-Avenir team, INM, INSERM , Montpellier university , Montpellier , France. 4 Clinical Neurosciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom 5 Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Québec, Canada 6 Department of Psychiatry and Neuroscience, Laval University, Quebec, Canada. 7 CERVO Brain Research Center, 2601 Chemin de la Canardière, Québec, QC, G1J 2G3, Canada 8 Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland. 9 Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, 10962, USA. 10Departments of Psychiatry, New York University School of Medicine, New York, NY, 10016, 11 Neuroscience Institute, New York University School of Medicine, New York, NY, 10016, USA. 12Department of Cell Biology, New York University School of Medicine, New York, NY, 10016, USA 13 University College London Queen Square Institute of Neurology, London, UK 14 UK Dementia Research Institute at University College London 15 Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden 16 Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden 17 UK Dementia Research Institute at Imperial College, London * Co-authors ordered alphabetically Address for correspondence: Prof.
    [Show full text]
  • Value of Systematic Genetic Screening of Patients with Amyotrophic Lateral
    Neurodegeneration J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2020-325014 on 14 February 2021. Downloaded from Original research Value of systematic genetic screening of patients with amyotrophic lateral sclerosis Stephanie R Shepheard ,1 Matthew D Parker,1 Johnathan Cooper- Knock ,1 Nick S Verber,1 Lee Tuddenham,1 Paul Heath,1 Nick Beauchamp,2 Elsie Place,2 Elizabeth S A Sollars,2 Martin R Turner ,3 Andrea Malaspina,4 Pietro Fratta,5,6 Channa Hewamadduma,7 Thomas M Jenkins ,1 Christopher J McDermott ,1 Dennis Wang,8 Janine Kirby,1 Pamela J Shaw ,1,7 on behalf of the Project MINE Consortium ► Additional material is ABSTRACT mild cognitive impairment, with approximately published online only. To view, Objective The clinical utility of routine genetic 5% progressing to clinically recognised fronto- please visit the journal online 1 (http:// dx. doi. org/ 10. 1136/ sequencing in amyotrophic lateral sclerosis (ALS) is temporal dementia (FTD). While the majority of jnnp- 2020- 325014). uncertain. Our aim was to determine whether routine ALS cases are considered sporadic (sALS), 5%–10% targeted sequencing of 44 ALS- relevant genes would have been shown to be familial, usually with auto- For numbered affiliations see have a significant impact on disease subclassification somal dominant inheritance, and the genetic cause end of article. and clinical care. of approximately 60%–70% of familial ALS (fALS) 2 Methods We performed targeted sequencing of a 44- cases has now been identified. The most common Correspondence to Professor Pamela J Shaw, gene panel in a prospective case series of 100 patients genetic cause of ALS is due to expansion of a Sheffield Institute for with ALS recruited consecutively from the Sheffield GGGGCC (G4C2) hexanucleotide repeat in the Translational Neuroscience, The Motor Neuron Disorders Clinic, UK.
    [Show full text]
  • DLL1- and DLL4-Mediated Notch Signaling Is Essential for Adult Pancreatic Islet
    Page 1 of 41 Diabetes DLL1- and DLL4-mediated Notch signaling is essential for adult pancreatic islet homeostasis (running title –Role of Delta ligands in adult pancreas) Marina Rubey1,2,6*, Nirav Florian Chhabra1,2*, Daniel Gradinger1,2,7, Adrián Sanz-Moreno1, Heiko Lickert2,4,5, Gerhard K. H. Przemeck1,2, Martin Hrabě de Angelis1,2,3** 1 Helmholtz Zentrum München, Institute of Experimental Genetics and German Mouse Clinic, Neuherberg, Germany 2 German Center for Diabetes Research (DZD), Neuherberg, Germany 3 Chair of Experimental Genetics, Centre of Life and Food Sciences, Weihenstephan, Technische Universität München, Freising, Germany 4 Helmholtz Zentrum München, Institute of Diabetes and Regeneration Research and Institute of Stem Cell Research, Neuherberg, Germany 5 Technische Universität München, Medical Faculty, Munich, Germany 6 Present address Marina Rubey: WMC Healthcare GmbH, Munich, Germany 7 Present address Daniel Gradinger: PSI CRO AG, Munich, Germany *These authors contributed equally **Corresponding author: Prof. Dr. Martin Hrabě de Angelis, Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Experimental Genetics, Ingolstädter Landstr.1, 85764 Neuherberg, Germany. Phone: +49-89-3187-3502. Fax: +49- 89-3187-3500. E-mail address: [email protected] Word count – 4088 / Figures – 7 Diabetes Publish Ahead of Print, published online February 6, 2020 Diabetes Page 2 of 41 Abstract Genes of the Notch signaling pathway are expressed in different cell types and organs at different time points during embryonic development and adulthood. The Notch ligand Delta- like 1 (DLL1) controls the decision between endocrine and exocrine fates of multipotent progenitors in the developing pancreas, and loss of Dll1 leads to premature endocrine differentiation.
    [Show full text]
  • The Dual Role of Micrornas in Colorectal Cancer Progression
    International Journal of Molecular Sciences Review The Dual Role of MicroRNAs in Colorectal Cancer Progression Lei Ding 1,2,†, Zhenwei Lan 1,2,†, Xianhui Xiong 1,2, Hongshun Ao 1,2, Yingting Feng 1,2, Huan Gu 1,2, Min Yu 1,2 and Qinghua Cui 1,2,* 1 Lab of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming 650091, China; [email protected] (L.D.); [email protected] (Z.L.); [email protected] (X.X.); [email protected] (H.A.); [email protected] (Y.F.); [email protected] (H.G.); [email protected] (M.Y.) 2 Key Lab of Molecular Cancer Biology, Yunnan Education Department, Kunming 650091, China * Correspondence: [email protected]; Tel.: +86-871-65031412 † These authors contributed equally to this work. Received: 29 August 2018; Accepted: 13 September 2018; Published: 17 September 2018 Abstract: Colorectal cancer (CRC) is responsible for one of the major cancer incidence and mortality worldwide. It is well known that MicroRNAs (miRNAs) play vital roles in maintaining the cell development and other physiological processes, as well as, the aberrant expression of numerous miRNAs involved in CRC progression. MiRNAs are a class of small, endogenous, non-coding, single-stranded RNAs that bind to the 3’-untranslated region (30-UTR) complementary sequences of their target mRNA, resulting in mRNA degradation or inhibition of its translation as a post-transcriptional regulators. Moreover, miRNAs also can target the long non-coding RNA (lncRNA) to regulate the expression of its target genes involved in proliferation and metastasis of CRC. The functions of these dysregulated miRNAs appear to be context specific, with evidence of having a dual role in both oncogenes and tumor suppression depending on the cellular environment in which they are expressed.
    [Show full text]